No one with HIV infection has been cured, regardless of the development of effective antiretroviral therapy (ART). Nevertheless, stable remission or cure of infection is the ultimate goal of HIV therapy. The difficulties of lifelong therapy make it imperative to understand the obstacles to eradication of HIV infection, and to attempt to overcome them. In addition to improved antivirals, agents that induce expression of latent HIV but do not enhance de novo infection are needed. Chromatin remodeling histone deacetylase enzymes play a critical role in HIV latency, and HDAC inhibitors (HDACi) augment HIV promoter and viral expression without global T cell activation or increased de novo HIV infection. To evaluate HDACi and other reagents that interrupt HIV latency, Project 3 will test candidate compounds provided by Project 1 in an iterative system using a novel primary T cell assay, and an ex vivo outgrowth assay in the primary resting CD4+ cells of aviremic, ART-treated patients. Lead compounds validated in this project will undergo animal model testing in Project 2, and then pilot human studies in Project 3. Progress toward these goals could significantly alter the approach to the treatment of HIV infection. Specific Aim 1: To use Jurkat and primary T-cell models to evaluate anti-latency therapeutics and define their mechanisms of action. Candidate reagents will be evaluated for their effects on the HIV LTR chromatin structure, transcriptional processivity, and viral expression. Specific Aim 2: To evaluate persistent resting CD4+ T cell infection in ART-suppressed HIV+ patients treated with intensified ART and reagents that disrupt proviral quiescence. The effects of potential anti-latency therapies will be measured by monitoring replication-competent HIV recovered from resting CD4+ T cells donated by ART-treated, aviremic HIV-infected volunteers and by a supersensitive assay of plasma HIV RNA.